9MGN

Crystal structure of PRMT5:MEP50 in complex with MTA and compound 41

これはPDB形式変換不可エントリーです。

9MGN の概要

• エントリーDOI: 10.2210/pdb9mgn/pdb
• 分子名称: Protein arginine N-methyltransferase 5, Methylosome protein 50, 2-(cyclobutylamino)-N-[(2S)-2-hydroxy-3-{6-[(1H-pyrazol-4-yl)methoxy]-3,4-dihydroisoquinolin-2(1H)-yl}propyl]pyridine-4-carboxamide, ... (7 entities in total)
• 機能のキーワード: methyltransferase, inhibitor, mtap-null, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 112616.17

構造登録者

Whittington, D.A. (登録日: 2024-12-11, 公開日: 2025-03-05)

主引用文献

Cottrell, K.M.,Whittington, D.A.,Briggs, K.J.,Jahic, H.,Ali, J.A.,Amor, A.J.,Gotur, D.,Tonini, M.R.,Zhang, W.,Huang, A.,Maxwell, J.P.
MTA-Cooperative PRMT5 Inhibitors: Mechanism Switching Through Structure-Based Design.
J.Med.Chem., 68:4217-4236, 2025

PubMed Abstract: Deletion of the gene leads to accumulation of the substrate of the MTAP protein, methylthioadenosine (MTA). MTA binds PRMT5 competitively with S-adenosyl-l-methionine (SAM), and selective inhibition of the PRMT5•MTA complex relative to the PRMT5•SAM complex can lead to selective killing of cancer cells with deletion. Herein, we describe the discovery of novel compounds using structure-based drug design to switch the mechanism of binding of known, SAM-cooperative PRMT5 inhibitors to an MTA-cooperative binding mechanism by occupying the portion of the SAM binding pocket in PRMT5 that is unoccupied when MTA is bound and hydrogen bonding to Arg368, thereby allowing them to selectively target -deleted cancer cells.

PubMed: 39919252
DOI: 10.1021/acs.jmedchem.4c01998

実験手法

X-RAY DIFFRACTION (2.82 Å)